Chronic Myelogenous Leukemia (CML) is a hematopoietic stem cell disorder triggered by expression of the BCR-ABL oncogene from the t(9;22) chromosomal translocation (the Philadelphia Chromosome). BCR- ABL drives apoptosis resistance and cytokine-independent proliferation in leukemic cells by activating the phosphatidylinositol 3'-kinase (PI3K)/Akt pathway. The tyrosine kinase inhibitor imatinib (Gleevec) is an effective treatment for CML patients in early stages of the disease. However, residual BCR-ABL+ cells survive imatinib treatment, permitting the development of drug-resistant mutations and resumption of disease progression. To achieve more efficient killing of BCR-ABL+ cells and, thus, curative chemotherapy in CML, new strategies to augment imatinib-induced apoptosis are required. Akt represses apoptosis by activating cellular glycolysis. Interruptions in Akt-induced glycolytic metabolism prevent Akt-dependent cell survival, restoring homeostatic control of apoptosis in cancer cells despite active Akt signal transduction. The signaling pathway that coordinates Akt metabolic and survival signals is poorly defined. Preliminary data in this proposal show that Akt signals increased metabolism and survival through the downstream protein kinase S6K1. Interestingly, S6K1 is also a negative regulator of upstream elements in the PI3K/Akt pathway, acting in a negative feedback loop to modulate Akt signaling. Thus S6K1 has both oncogenic and tumor suppressor activities, inducing survival metabolism downstream of Akt while simultaneously suppressing Akt signaling through negative feedback. An emerging approach for counteracting the Akt survival pathway is based on interfering with Akt- induced metabolism by inactivating S6K1. Research proposed here will explore the therapeutic implications of inactivating S6K1 in experiments that test the oncogenic vs. tumor suppressor functions of S6K1 in leukemia. Specifically, the role of S6K1 in BCR-ABL-induced metabolism and apoptosis resistance will be determined using S6K1-deficient mice in a mouse model of CML. A parallel set of experiments will assess the effects of S6K1-deficiency in a mouse model of Akt leukemogenesis where Akt is directly activated through the inducible deletion of PTEN, an upstream regulator of Akt. Results from mouse models of leukemia will then be used to design and test novel approaches for enhancing apoptotic responses in leukemic cells by interfering with the Akt metabolic program. The results of our experiments will provide mechanistic and functional insights for enhancing therapeutic efficacy in CML and other cancers with activated Akt. PUBLIC HEALTH REVANCE Chronic Myelogenous Leukemia (CML) is a cancer of the blood that accounts for approximately 10% of adult leukemia. The currently preferred drug treatment, imatinib mesylate, effectively kills most cancer cells, but the remaining cells can acquire drug-resistance and cause relapse. This research project explores a new approach to augment the cell-killing ability of the current treatment by specifically interfering with cancer-cell metabolism. Results of these experiments will lead to novel strategies for eliminating the residual cancer cells that can cause relapse in leukemia.